A major problem in tumor immunotherapy is the fact that tumor specific CD8 T cells are restrained by self- tolerance and normal mechanisms of immune homeostasis. The goal of this project is to enhance tumor eradication by low avidity CD8 T cells specific for tumor antigens. These experiments will use RIP-Tag2HA mice in which autochthonous insulinomas develop and express a surrogate tumor antigen, the influenza hemagglutinin (HA), and 3 different lines of TCR transgenic mice specific for HA epitopes. Clone 1 and Clone 4 TCR transgenics express TCR derived from CD8 cells that recognized the same Kd restricted epitope of HA with low or high affinity, respectively. SFE TCR transgenics express a CD4 derived TCR specific for a different epitope of HA restricted to I-Ed. Two different experimental strategies will be pursued to enhance tumor eradication. Aim 1 describes the development of a new type of adjuvant consisting of complexes of IL-2 bound by anti-IL-2 (IL-2c), combined with a well tolerated inflammatory adjuvant, poly(I:C). These synergize to promote tumor eradication by low avidity tumor specific Clone 1 CD8 cells. Experiments under Aim 1 will investigate the molecular basis for the ability of this combination of adjuvants to promote survival and tumor eradication by low avidity, tumor specific CD8 cells. The second strategy is the use of tumor specific CD4 cells to assist low avidity CD8 cells in infiltration and destruction of tumor cells. Aim 2 will examine why SFE CD4 cells, but not Clone 1 CD8 cells, are efficiently recruited to the tumor milieu, and how CD4 cells promote recruitment of Clone 1. PUBLIC HEALTH RELEVANCE The goal of cancer immunotherapy is to use our immune system to destroy cancer cells. The goal of this project is to improve cancer vaccines and immunotherapy so that they may be used as a reliable method for treatment of cancer patients.